Process of producing phenethylamine derivatives

ABSTRACT

Phenethylamine derivatives shown by the general formula ##STR1## wherein Ro represents a lower alkyl group; R 1  represents a lower alkyl group or a lower alkoxy group; R 2  represents hydrogen atom or a hydroxyl group; R 3  and R 4  each represents hydrogen atom or a lower alkyl group; R 5  represents hydrogen atom or a lower alkoxy group; X represents oxygen atom or a methylene group; m is an integer of 1 -3; and n is an integer of 0-2 and the acid addition salts thereof. 
     These compounds exhibit a strong α-adreneregic blocking action and are useful as an antihypertensive agent.

This application is a continuation of application Ser. No. 208,804 filedJune 17, 1988 which is a continuation of Ser. No. 082,382 filed Aug. 6,1987, in turn a continuation of Ser. No. 894,464, filed July 31, 1986,in turn a continuation of Ser. No. 690,398, filed Jan. 9, 1985, in turna continuation of Ser. No. 517,734, July 28, 1983 in turn a continuationof Ser. No. 285,782, filed July 22, 1981, all now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel phenethylamine derivatives and the acidaddition salts thereof, and more particularly to novel phenethylaminederivatives and the acid addition salts thereof exhibiting a strongα-adrenergic blocking action and useful as an antihypertensive agent.

2. Description of the Prior Art

U.K. Pat. No. 1,321,701 discloses a series of compounds represented bythe following formula ##STR2## wherein R₁ is RS--, RSO-- or RSO₂ --(wherein R is an alkyl of C₁ -C₁₀); R₂ and R₃ each is hydrogen, an alkylof C₁ -C₃, an alkoxy of C₁ -C₄, or an alkylthio of C₁ -C₄ ; R₄represents hydrogen or an alkyl of C₁ -C₄ ; and R₅ and R₆ each is alkylof C₁ -C₁₆ which may a substituted by a phenyl group or substitutedphenyl group and states that these compounds exhibit a β-adrenergicblocking action, a peripheral vasodilating effect, an antiarrhythmiceffect and a hypotensitive effect.

Belgian Pat. No. 856,055 discloses a series of compounds shown by theformula ##STR3## wherein Z is OH or H; R₁, R₂ and R₃ each is H or alower alkyl group; n is 1-3; Ar is a phenyl group which may besubstituted by 1 to 3 halogen atoms, lower alkyl groups, lower alkoxygroups or OHs; Q is lower alkyl-S(O)_(m) (m is 0, 1, or 2); and Y is H,a lower alkanoyl group, an aroyl group, a benzenesulfonyl group, or atoluenesulfonyl group and states that these compounds exhibit aβ-adrenergic blocking activity, a vasodilating activity, anantiarrhythmic effect and a hypotensive effect.

SUMMARY OF THE INVENTION

An object of this invention is to provide pharmacologically usefulcompounds which possess a hypotensive activity based on an α-adrenergicblocking action and can be used as an antihypertensive agent.

Another object of this invention is to provide a process of producingthe aforesaid pharmacologically useful compounds.

According to this invention, there are provided phenethylaminederivatives shown by formula I and the acid addition salts thereof##STR4## wherein Ro represents a lower alkyl group; R₁ represents alower alkyl group or a lower alkoxy group; R₂ represents hydrogen atomor a hydroxyl group; R₃ and R₄ each represents hydrogen atom or a loweralkyl group; R₅ represents a hydrogen atom or a lower alkoxy group; Xrepresents oxygen atom or a methylene group; m represents an integer of1-3; and n represents an integer of 0-2.

These compounds of this invention are useful as antihypertensive agents.

According to another embodiment of this invention, the compounds shownby the above-described formula I can be prepared as follows:

(1). A phenethylamine derivative shown by the general formula ##STR5##wherein R_(o), R₁, R₃, R₄, R₅, X, m, and n have the same significance asdefined in formula I can be obtained by reacting the halohydrin shown bythe formula ##STR6## wherein hal. represents halogen atom and Ro, R₁, R₃and n have the same significance as defined above or an epoxide shown bythe formula ##STR7## wherein Ro, R₁, R₃, and n have the samesignificance as defined above and an amine shown by the formula ##STR8##wherein Z represents a hydrogen atom or a benzyl group, and R₄, R₅, X,and m have the same significance as defined above and, when Z is abenzyl group, removing the group from the product.

(2). A phenethylamine derivative shown by the formula ##STR9## whereinR_(o), R₁, R₃, R₄, R₅, X, m, and n have the same significance as informula I can be prepared by reducing an aminoketone shown by theformula ##STR10## wherein R_(o), R₁, R₃, R₄, R₅, X, m, and n have thesame significance as defined in formula I and, when Z is a benzyl group,removing the group from the reduction product.

(3). A phenethylamine derivative shown by the formula ##STR11## whereinR_(o), R₁, R₃, R₄, R₅, X, m, and n have the same significance as definedin formula I can be prepared by condensing a ketone shown by the formula##STR12## wherein R_(o), R₁, R₃ and n have the same significance asabove defined and the amine shown by an formula ##STR13## wherein R₄,R₅, X and m have the same significance as above defined, reducing thecondensation product, and, when n is 0, further the product with anoxidizing agent.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Now, the term "lower" used in the above-described formulae means astraight or branched carbon chain having 1 to 5 carbon atoms. Therefore,for example, a lower alkyl group includes methyl group, ethyl group,propyl group, butyl group, pentyl group, isobutyl group, etc., and alower alkoxy group includes methoxy group, ethoxy group, propoxy group,butoxy group, etc. Also, in the above-described formulae, the R₅ groupswhich are substituents of the benzene ring may be disposed at anyposition of ortho, meta, and para to the side chain. Furthermore, sincea compound of formula [I] of this invention can form readily the saltthereof and contains asymmetric carbon atom(s), the compounds of thisinvention includes the salts thereof, the racemic compound thereof, amixture of the racemic compounds, and each optical active substance.

The compounds of formula [I] and the acid addition salts thereofprovided by the present invention exhibit α-adrenergic blocking actions.Therefore, they can be utilized for various treatments. For example,they can be used as useful agents for the treatment of hypertension,congestive heart failure, angina pectoris, lower urinary tractdysfunction, prostatic hypertrophy, pheochromocytoma and peripheralvascular disorders.

The pharmacological effects of the compounds of this invention weredetermined by the following experiments. The effects of the typicalcompounds of this invention were compared with those of5-{1-hydroxy-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide(referred to as "Compound A") which is one of the typical compoundsdisclosed in British Pat. No. 2,006,772 and phentolamine.

A. α-Adrenergic blocking action:

The blood pressure was measured in the rats anesthetized with urethaneand treated with pentolinium. The effects of the test samples(intravenous injection) to antagonize the hypertensive response tophenylephrine (10 μg/Kg i.v.) were measured and the results were shownin Table I.

B. Antihypertensive effects in spontaneously hypertensive rats:

Oral administration:--The systolic blood pressure was measuredindirectly by the tail cuff method using a programmedelectrosphygmanometer (Nacro-Bio-Systems Inc., PE-300) on spontaneouslyhypertensive rats having the systolic blood pressure of higher than 150mmHg, the results being shown in Table II.

                  TABLE I                                                         ______________________________________                                        α-blocking activity                                                     compounds of this                                                                            α-blocking activity (rat)                                invention (Ex. No.)                                                                          ED.sub.50 (mg/kg) i.v.                                         ______________________________________                                        5              0.045                                                          6              0.021                                                          8              0.0019                                                         12             0.00014                                                        known compounds:                                                              Compound A     0.032                                                          phentolamine   0.061                                                          ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        antihypertensive effect                                                                                 change in systolic                                                            blood pressure                                      compounds of this         (mm Hg) at stated                                   invention (Ex. No.)                                                                          dose (mg/kg)                                                                             dose P.O.                                           ______________________________________                                        5              30         -60                                                 6              30         -64                                                 8              30         -48                                                 12             30         -58                                                 known compounds:                                                              Compound A     30         -30                                                 phentolamine   30         -53                                                 ______________________________________                                    

The clinical administration of the compounds of this invention isusually intravenous injection or orally as the free base or to acidaddition salt thereof (e.g., hydrochloride, oxalates, sulfates,maleates, acetates, fumarates, lactates, citrates, etc.,). It is properto administer about 0.01 mg per single dose of the compound severaltimes per day in case of intravenous administration or about 1000 mg ofthe compound in two or three times per day in case of oraladministration. The compounds of this invention may be formulated intoordinary dosage forms such as, for example, tablets, capsules, pillssolutions, etc., and in these cases, the medicaments can be prepared byconventional method using usual medical excipients.

The compounds of this invention shown by formula [I] can be produced bythe following processes. ##STR14##

Step 1: Usually the process is performed by reacting the halohydrin offormula II₁ or the epoxide of formula II₂ and an equimolar amount toexcessive amount of the amine of formula III in a non-solvent or anorganic solvent. As the organic solvent used in the reaction, there are,for example, ethanol, toluene, methyl ethyl ketone, acetonitrile,tetrahydrofuran, dimethyl formamide, etc. Also, the reaction proceeds atroom temperature to under heating but for promoting the reaction, thereaction is usually performed under heating or under refluxing.

Step 2: When Z is a benzyl group in compound I₁ ' shown above, thebenzyl group is removed by performing an ordinary catalytichydrogenation using for example palladium carbon as a catalyst.

The isolation and purification of the reaction product of formula I₁ 'or I₁ is performed by an ordinary operation such as filtration,extraction by solvent, column chromatography, recrystallization, etc.##STR15##

Step 1: This step can be practised under the reaction conditions as inStep 1 of Process A.

Step 2: This step can be performed in an organic solvent such asmethanol, ethanol, toluene, acetonitrile, tetrahydrofuran, etc., undercooling or at room temperature using a complex metal hydride such assodium borohydride, diborane, etc., and when the reduction is performedin the presence of a ordinary hydrogenation catalyst such as palladiumcarbon, etc., the removal of the benzyl group can be performedsimultaneously.

Step 3: The step can be performed under the same reaction conditions asin Step 2 of Process A. ##STR16##

Step 1: Compounds of formula I₂ is obtained by condensing a compound offormula VI and a compound of formula III in an organic solvent such asmethanol, ethanol, toluene, acetonitrile, tetrahydrofuran, etc., andthen reducing the condensation product in the presence of PtO₂ or aRaney nickel catalyst or with NaBH₄, etc.

Step 2: A sulfinyl compound of formula I₃ wherein n is 1 can be obtainedby treating the compound of formula I₂ in an organic solvent such asmethanol, ethanol, etc., using a proper oxidizing agent such as, forexample, hydrogen peroxide aqueous solution (10-50%), sodiummeta-periodate, etc. Also, the sulfonyl compound of formula I₄ wherein nis 2 can be obtained by treating together with an oxidizing agent(hydrogen peroxide aqueous solution, etc.,) in an acid solvent such asformic acid, acetic acid, etc.

Then, the production process of this invention will be further describedin the following examples. In addition, the raw materials orintermediates used in the process of this invention include novelcompounds and examples of the productions of these compounds are alsoshown in the following reference examples.

Reference example 1

(a). Into a suspension of 300 g of stannous chloride di-hydrate in 1100ml of glacial acetic acid, was introduced hydrogen chloride gas withstirring until the suspension became transparent and then a solution of50 g of 3-chlorosulfonyl-4-methylacetophenone dissolved in 100 ml ofglacial acetic acid was added thereto dropwise at 25°-30° C. Afterfurther stirring the mixture for one hour, 2,000 ml of water was addedto the reaction mixture and the product was extracted with 1,000 ml ofbenzene. After washing the benzene extract with water, benzene wasdistilled off and the residue was distilled under reduced pressure toprovide 37 g of 3-mercapto-4-methylacetophenone having a boiling pointof 105°-115° C./2 mm Hg.

(b). A mixture of 31 g of 3-mercapto-4-methylacetophenone, 31 g ofanhydrous potassium carbonate, 29 g of methyl iodide, and 360 ml ofacetone was stirred for 3 hours at room temperature, the reactionmixture obtained was filtered, and the filtrate was evaporated todryness. The residue formed was dissolved in benzene and after washingthe solution obtained with water, benzene was distilled off. Then, theresidue was distilled under reduced pressure to provide 29 g of4-methyl-3-methylthioacetophenone having a boiling point of 96°-105°C./0.7 mm Hg.

(c). In 200 ml of carbon tetrahcloride was dissolved 20 g of4-methyl-3-methylthioacetophenone and then 18 g of bromine was addeddropwise to the solution with stirring at room temperature. After thereaction was over, carbon tetrachloride was distilled off and theresidue obtained was recrystallized from carbon tetrachloride to provide18 g of 4'-methyl-3'-methylthio-2-bromoacetophenone having a meltingpoint of 85°-86° C.

(d). To a mixture of 18 g of 4'-methyl-3'-methylthio-2-bromoacetophenoneand 300 ml of methanol was gradually added 8 g of sodium borohydrate andthereafter the mixture was stirred for one hour at 40°-50° C. Afterdistilling off methanol from the reaction mixture, 200 ml of water wasadded to the residue and the product was extracted with 300 ml ofbenzene. Then, benzene was distilled off and the residue formed waspurified by a silica gel column chromatography (eluant benzene) toprovide 8.5 g of oily 4-methyl-3-methylthiostyrene oxide.

Nuclear magnetic resonance spectra (CDCl₃)

    ______________________________________                                        δ:                                                                               ##STR17##                                                                    2.44 (3H, s, C .sub.--H.sub.3S)                                                ##STR18##                                                                     ##STR19##                                                            ______________________________________                                    

Reference example 2

(a). To an aqueous solution of 400 g of sodium sulfite-7H₂ O dissolvedin 615 ml of water was added 81 g of3-chlorosulfonyl-4-methylacetophenone and the mixture was stirred for 30minutes at 50°-55° C. After cooling, the reaction mixture was acidifiedby the addition of concentrated hydrochloric acid and extracted with1,000 ml of ethyl acetate. The ethyl acetate layer obtained was washedwith 500 ml of water, and after drying by anhydrous sodium sulfate, thesolvent was distilled off to provide 50 g of a colorless caramel-likepowder of 5-acetyl-2-methylbenzenesulfinic acid. The product wasdissolved in 500 ml of 60% ethanol and after adding thereto 8 g ofsodium hydroxide and 145 g of methyl iodide, the mixture was refluxedfor 15 hours. After the reaction was over, the solvent was distilled offand after adding water to the residue, the product was extracted with1,000 ml of ethyl acetate. The ethyl acetate layer obtained was washedin succession with 300 ml of an aqueous 5% sodium thiosulfate solution,300 ml of an aqueous 5% sodium hydroxide solution, and then 300 ml ofwater, and after drying with anhydrous magnesium sulfate, the solventwas distilled off to provide 44 g of methyl5-acetyl-2-methylbenznesulfinate.

(b). In 200 ml of chloroform was dissolved 21.2 g of methyl5-acetyl-2-methylbenzenesulfinate and then 16.8 g of bromine was addeddropwise to the solution with stirring at 40° C. After the reaction wasover, the reaction mixture was added to 500 ml of water and thechloroform layer formed was recovered, washed with a saturated aqueoussodium hydrogen-carbonate solution, and dried with anhydrous magnesiumsulfate. Then, the solvent was distilled off and the crude crystalsformed were recrystallized from ethanol to provide 26 g of methyl5-bromoacetyl-2-methylbenzenesulfinate having a melting point of123°-125° C.

Reference example 3

(a). While ice-cooling a suspension of 84 g of stannous chloride --2H₂ Oin 320 ml of glacial acetic acid with stirring until a transparentsolution was obtained, hyrochloric acid gas was introduced into thesolution and then 14.3 g of 3-chlorosulfonyl-4-methoxyphenylacetone wasadded to the solution at 25°-30° C. After further stirring the mixtureat room temperature for 30 minutes, the reaction mixture obtained waspoured into 320 ml of concentrated hydrochloric acid and after dilutingthe mixture with 640 ml of water, the product was extracted with 400 mlof chloroform. The chloroform layer formed was washed with water andthen chloroform was distilled off to provide 10 g of oily3-mercapto-4-methoxyphenylacetone.

(b). A mixture of 10 g of 3-mercapto-4-methoxyphenylacetone, 9 g ofanhydrous potassium carbonate, 42 g of methyl iodide, and 50 ml ofmethyl ethyl ketone was stirred under refluxing for 20 hours, and aftercooling, the reaction mixture was filtered. The filtrate obtained was,then, evaporated to dryness. The residue formed was dissolved in ethylacetate and after washing the solution obtained with water, ethylacetate was distilled off and the crude crystals obtained wererecrystallized from a mixture of n-hexane and ether to provide 9 g of3-methylthio-4-methoxyphenylacetone having a melting point of 74°-75° C.

(c). By following the same procedure as in above process (b) usingisopropyl iodide as an alkylating agent, oil4-isopropylthio-3-methoxyphenylacetone was obtained. The productobtained shows the following nuclear magnetic resonance spectra.

Nuclear magnetic resonance spectra (CDCl₃):

    ______________________________________                                               δ:                                                                           ##STR20##                                                                    2.12 (3H, s, COC .sub.--H.sub.3)                                               ##STR21##                                                                    3.60 (2H, s, C .sub.--H.sub.2 CO)                                              ##STR22##                                                         ______________________________________                                    

Example 1 ##STR23##

A mixture of 6 g of 4-methyl-3-methylthiostyrene oxide and 7 g of3-(4-methoxyphenyl)-1-methylpropylamine was heated to 115° C. for 3hours. After the reaction was over, the reaction mixture was dissolvedin 100 ml of benzene and after washing twice each time with 200 ml ofwater, the benzene layer was purified by a silica gel columnchromatography (eluate: a mixture of benzene, ethyl acetate, andmethanol (4:3:1 by volume ratio) to provide 3.5 g of amorphousα-{[3-(4-methoxyphenyl)-1-methylpropylamino]methyl}-4-methyl-3-methylthiobenzenemethanol.

The product has the following physicochemical properties:

(1) Amorphous form

(ii) Elemental analysis for C₂₁ H₂₉ NO₂ S:

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             70.16         8.13    3.90                                          Found:    69.98         8.20    3.75                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spectra (CDCl₃):

    ______________________________________                                               δ:                                                                          1.50 (3H, d, C .sub.--H.sub.3CH)                                               ##STR24##                                                                    2.37 (3H, s, C .sub.--H.sub.3S)                                               3.79 (3H, s, C .sub.--H.sub.3O)                                               4.70 (1H, m, C .sub.--HOH)                                         ______________________________________                                    

By following substantially the same procedure as in Example 1, thecompounds shown in following Example 2 and Example 3 were obtained.

Example 2 ##STR25##

α-{[(1-Methyl-3-phenyl)propylamino]methyl}-4-methyl-3-methylthiobenzenemethanol.

Physicochemical properties:

(i) Melting point: 48°-60° C.

(ii) Elemental analysis for C₂ OH₂₇ NOS:

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             72.90         8.26    4.25                                          Found:    72.80         8.26    4.36                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spectra (CDCl₃):

    ______________________________________                                               δ:                                                                          1.10 (3H, d, C .sub.--H.sub.3CH)                                               ##STR26##                                                                    2.42 (3H, s, C .sub.--H.sub.3S)                                               4.61 (1H, q, C .sub.--HOH)                                         ______________________________________                                    

Example 3 ##STR27##

α-{[2-(2-Methoxyphenoxy)ethylamino]methyl}-4-methyl-3-methylthiobenzenemethanolhydrochloride.

Physicochemical properties:

(i) Melting point: 97°-98° C.

(ii) Elemental analysis for C₁₉ H₂₅ NO₃ S+HCl:

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             59.44         6.83    3.65                                          Found:    59.20         6.92    3.42                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spectra (CDCl₃):

    ______________________________________                                               δ:                                                                           ##STR28##                                                                    2.37 (3H, s, C .sub.--H.sub.3S)                                               3.76 (3H, s, C .sub.--H.sub.3O)                                               4.84 (1H, m, C .sub.--HOH)                                         ______________________________________                                    

Example 4 ##STR29##

In 70 ml of methanol was dissolved 2.5 g ofα-{[3-(4-methoxyphenyl)-1-methylpropylamino]-methyl}-4-methyl-3-methylthiobenzenemethanoland then 8 ml of an aqueous 30% hydrogen peroxide solution was addeddropwise to the solution under ice-cooling. After allowing the reactionmixture to stand overnight the at room temperature, methanol wasdistilled off and after adding 50 ml of water to the residue, theproduct was extracted with ethyl acetate. The ethyl acetate layer formedwas dried by anhydrous magnesium sulfate and after distilling off thesolvent, the residue was purified with a silica gel columnchromatography (eluate: a mixture of benzene, ethyl acetate, andmethanol (4:3:1 by volume ratio) to provide 2.0 g of the amorphouscaramel-like powder ofα-{[3-(4-methoxyphenyl)-1-methylpropylamino]methyl}-4-methyl-3-methylsulfinylbenzenemethanol.

The product has the following physicochemical properties:

(i) Amorphous form

(ii) Elemental analysis for C₂₁ H₂₉ NO₃ S:

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             67.17         7.78    3.73                                          Found:    67.38         7.69    3.52                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spcetra (CDCl₃):

    ______________________________________                                               δ:                                                                          1.04 (3H, d, C .sub.--H.sub.3CH)                                               ##STR30##                                                                    2.79 (3H, s, C .sub.--H.sub.3SO)                                              3.73 (3H, s, C .sub.--H.sub.3O)                                               4.58 (1H, q, C .sub.--HOH)                                         ______________________________________                                    

By following substantially the same procedure as in Example 4, thecompound shown in following example 5 was obtained.

Example 5 ##STR31##

α-{[2-(2-Methoxyphenoxy)ethylamino]methyl}-4-methyl-3-methylsulfinylbenzenemethanoloxalate.

Physicochemical properties:

(i) Melting point: 182°-184° C.

(ii) Elemental analysis for C₁₉ H₂₅ NO₄ S+(COOH)₂ :

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             55.62         6.00    3.09                                          Found:    55.49         5.95    3.16                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spectra (CDCl₃)

    ______________________________________                                               δ:                                                                           ##STR32##                                                                    2.63 (3H, s, C .sub.--H.sub.3SO)                                              3.80 (3H, s, C .sub.--HO)                                                     4.96 (1H, m, C .sub.--HOH)                                         ______________________________________                                    

Example 6 ##STR33##

A mixture of 5.8 g of methyl 5-bromoacetyl-2-methylbenzenesulfinate, 160of methyl ethyl ketone, and 10.3 g ofN-benzyl-2(o-methoxyphenoxy)ethylamine was refluxed with stirring for 40minutes. After the reaction was over, the solvent was distilled off, 150ml of ethyl acetate was added to the residue formed, andN-benzyl-2-(2-methoxyphenoxy)ethylamine hydrobromide precipitated wasremoved by filtration. The solvent was distilled off from the filtrate,the residue obtained was dissolved in 125 ml of methanol, and 1.5 g ofsodium borohydide was added to the solution under ice-cooling.

The mixture was stirred for 2 hours at room temperature and thenmethanol was distilled off. After adding 100 ml of water to the residueformed, the product was extracted with 200 ml of ethyl acetate, theethyl acetate layer obtained was washed with water, and after drying byanhydrous magnesium sulfate, the solvent was distilled off to provide 10g of oilyα-{2-[N-benzyl-2-(2-methoxyphenoxy)ethylamino]methyl}-4-methyl-3-methoxysulfinylbenzenemethanol.The product was dissolved in 100 ml of methanol and after adding 0.8 gof 10% palladium carbon, the product was subjected to catalyticreduction at normal temperature and normal pressure. After the reactionwas over, palladium carbon was removed by filtration and the filtratewas evaporated to dryness. To the residue obtained was added a solutionof 1.7 g of oxalic acid dissolved in 17 ml of methanol and the mixturewas allowed to stand overnight at room temperature to provide 6 g ofcolorless crystals. The crystals were recrystallized from 30 ml ofmethanol to provideα-{[2-(2-methoxyphenoxy)ethylamino]methyl}-4-methyl-3-methoxysulfinylbenzenemethanoloxalate.

The product has the following physicochemical properties:

Melting point: 185°-188° C.

Elemental analysis for C₁₉ H₂₅ NO₅ S+(COOH)₂ :

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             53.72         5.80    2.98                                          Found:    53.62         5.76    3.09                                          ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSO):

    ______________________________________                                               δ:                                                                           ##STR34##                                                                    3.22 (3H, s, C .sub.--H.sub.3SO.sub.2)                                        3.71 (3H, s, C .sub.--H.sub.3O)                                               5.04 (1H, m, C .sub.--HOH)                                         ______________________________________                                    

Example 7 ##STR35##

A mixture of 8.4 g of 4-methoxy-3-methylthiophenylacetone, 6.7 g of2-methoxyphenoxyethylamine, and 150 ml of methanol was refluxed for 2hours. The reaction mixture was cooled to a temperature below 10° C. andafter adding 2.5 g of sodium borohydride to the reaction mixture withstirring at temperatures below 10° C., the mixture was further stirredfor 3 hours at room temperature. Then, the solvent was distilled offunder reduced pressure and after adding water to the residue, theproduct was extracted with ethyl acetate. The extract was washed withwater, dried by anhydrous magnesium sulfate, and then the solvent wasdistilled off to provide an oily product. The product was purified by asilica gel column chromatography (eluate: chloroform) to provide 8.5 gof4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole.The product (750 mg) was dissolved in 10 ml of methanol and after addingthereto a solution of 90 mg of anhydrous oxalic acid dissolved in 1 mlof methanol, the mixture was allowed to stand overnight at roomtemperature. The crystals thus formed were recovered by filtration andrecrystallized from ethanol to provide 600 mg of4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisoleoxalate having a melting point of 173°-174° C.

Physicochemical properties:

(i) Elemental analysis for C₂₀ H₂₇ NO₃ S+(COOH)₂ :

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             58.52         6.47    3.10                                          Found:    58.33         5.93    2.97                                          ______________________________________                                    

(ii) Nuclear magnetic resonance spectra (CDCl₃):

    ______________________________________                                        δ: 1.08        (3H, d, CH.sub.3 --CH)                                   2.38                 (3H, s, CH.sub.3 S--)                                    3.78                 (3H, s, CH.sub.3 --O--)                                  3.86                 (3H, s, CH.sub.3 --O--)                                  ______________________________________                                    

By following substantially the same procedure as in Example 7, thecompound shown in following Example 8 was obtained.

Example 8 ##STR36##

4-{2-[2-(2-Ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisolehydrochloride.

Physicochemical properties:

(i) Melting point: 88°-89° C.

(ii) Elemental analysis for C₂₁ H₂₉ NO₃ S+HCl+1/4H₂ O

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             59.91         7.42    3.33                                          Found:    59.74         7.45    3.45                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spectra (CDCl₃)

    ______________________________________                                        δ: 2.31         (3H, s, CH.sub.3 --S)                                   3.84                  (3H, s, CH.sub.3 --O)                                   4.44                  (2H, t, CH.sub.2 --O)                                   ______________________________________                                    

Example 9 ##STR37##

In 100 ml of a mixture of methanol and water (5:1) was dissolved 1.8 gof4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisoleand after adding dropwise thereto 10.5 ml of an aqueous solution of 0.5Msodium metaperoiodate at 0° C., the mixture was stirred overnight at 4°C. The crystals formed were removed by filtratation and the filtrate wasconcentrated under reduced pressure and the residue formed was purifiedby a silica gel column chromatography (eluate: a mixture of chloroformand methanol (97:3 by volume ratio) to provide 722 mg of oily4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisole.The product was dissolved in 10 ml of methanol and after adding theretoa solution of 252 mg of oxalic acid di-hydrate dissolved in 6 ml ofmethanol, the mixture was allowed to stand overnight at roomtemperature. The resulting crystaline material was recovered byfiltration and recrystallized from ethanol to provide 700 mg of4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisoleoxalate having a melting point of 172°-174° C.

The product has the following physicochemical properties:

(i) Elemental analysis for C₂₀ H₂₇ NO₄ S+(COOH)₂ :

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             56.52         6.25    3.00                                          Found:    56.17         6.25    3.01                                          ______________________________________                                    

(ii) Nuclear magnetic resonance spectra (d₆ -DMSO):

    ______________________________________                                        δ: 1.12        (3H, d, CH.sub.3 --CH)                                   2.68                 (3H, s, CH.sub.3 SO--)                                   3.76                 (3H, s, CH.sub.3 --O--)                                  3.84                 (3H, s, CH.sub.3 --O--)                                  ______________________________________                                    

Example 10 ##STR38##

In 30 ml of ethanol was dissolved 1.0 g of4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisolehydrochloride and then 0.5 g of an aqueous 35% hydrogen peroxidesolution was added to the solution with stirring. After stirring themixture for 18 hours at room temperature, ethanol was distilled offunder reduced pressure and the remaining sticky product was dispersed in20 ml of water and extracted with 100 ml of ethyl acetate. The ethylacetate layer was washed three times each time with 20 ml of water andafter acidifying the solution with 0.2 ml of concentrated hydrochloricacid, the solvent was distilled off under reduced pressure. Theremaining sticky material was applied to a silica gel columnchromatography and eluted using a mixture of ethyl acetate and methanol(4:1 by volume ratio). The sticky product obtained was crystallized bythe addition of 3 ml of isopropanol and the crystals thus formed wererecovered by filtration to provide 0.4 g of4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisolehydrochloride.

The product has the following physicochemical properties:

(i) Melting point: 154°-160° C.

(ii) Elemental analysis for C₂₁ H₂₉ NO₄ S+HCl:

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             58.93         7.06    3.27                                          Found:    58.64         7.07    3.41                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spectra (CDCl₃):

    ______________________________________                                        δ: 2.70         (3H, s, CH.sub.3 --SO)                                  3.82                  (3H, s, CH.sub.3 --O)                                   4.43                  (3H, t, CH.sub.2 --O)                                   ______________________________________                                    

Example 11 ##STR39##

In 18 ml of glacial acetic acid was dissolved 1.8 g of4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisoleand then 1.15 g of an aqueous 30% hydrogen peroxide solution was addeddropwise to the solution under ice-cooling. After heating the mixture to60° C. for one hour, 100 ml of water was added to the reaction mixtureand the product was extracted with ethyl acetate. The ethyl acetatelayer was washed with water, dried with anhydrous magnesium sulfate, andthen the solvent was distilled off. The residue obtained was purified bya silica gel column chromatography (eluate: a mixture of chloroform andmethanol (97:3 by volume ratio) to provide 1 g of oily4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfonyl)anisole.The produce was dissolved in 10 ml of methanol and after adding theretoa solution of 230 mg of anhydrous oxalic acid dissolved in 2 ml ofmethanol, the mixture was allowed to stand overnight at roomtemperature. The crystals thus formed were recovered by filtration andrecrystallized from methanol to provide 700 mg of4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfonyl)anisoleoxalate having a melting point of 194°-195° C.

The product has the following physicochemical properties:

(i) Elemental analysis for C₂₀ H₂₇ NO₅ S+(COOH)₂ :

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             54.65         6.04    2.90                                          Found:    54.48         6.06    3.09                                          ______________________________________                                    

(ii) Nuclear magnetic resonance spectra (d₆ -DMSO):

    ______________________________________                                        δ: 1.12        (3H, d, CH.sub.3 --CH)                                   3.16                 (3H, s, CH.sub.3 --SO.sub.2 --)                          3.72                 (3H, s, CH.sub.3 --O--)                                  3.92                 (3H, s, CH.sub.3 --O--)                                  ______________________________________                                    

By following substantially the same procedure as in Example 11, thecompounds shown in the following examples were obtained.

Example 12 ##STR40##

4-{2-[2-(2-Ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfonyl)anisolehydrochloride.

Physicochemical properties:

(i) Melting point: 193°-196° C.

(ii) Elemental analysis for C₂₁ H₂₉ NO₅ S+HCl:

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             56.81         6.81    3.15                                          Found:    56.53         6.82    3.23                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spectra (CDCl₃):

    ______________________________________                                        δ: 3.16        (3H, s, CH.sub.3 --SO.sub.2 )                            3.94                 (3H, s, CH.sub.3 --O)                                    4.44                 (2H, t, CH.sub.2 -- O)                                   ______________________________________                                    

Example 13 ##STR41##

4-{2-[2-(2-Methoxyphenoxy)ethylamino]-2-methylethyl}-2-(isopropylthio)anisoleoxalate.

Physicochemical properties:

(i) Melting point: 157°-158° C.

(ii) Elemental analysis for C₂₂ H₃₁ NO₃ S+(COOH)₂ :

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             60.11         6.94    2.92                                          Found:    60.10         7.05    2.84                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spectra (d₆ -DMSO):

    ______________________________________                                        δ:                                                                                 ##STR42##                                                                     ##STR43##                                                                     ##STR44##                                                          ______________________________________                                    

Example 14 ##STR45##

4-{2-[2-(2-Methoxyphenoxy)ethylamino]-2-methylethyl}-2-(isopropylsulfinyl)anisoleoxalate.

Physicochemical properties:

(i) Melting point: 146°-147° C.

(ii) Elemental analysis for C₂₂ H₃₁ NO₄ S+(COOH)₂ :

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calcuated:                                                                              58.17         6.71    2.83                                          Found:    58.17         6.73    2.94                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spectra (d₆ -DMSO):

    ______________________________________                                        δ:                                                                             ##STR46##                                                                     ##STR47##                                                                     ##STR48##                                                              ______________________________________                                    

Example 15 ##STR49##

4-{2-[2-(2-Methoxyphenoxy)ethylamino]-2-methylethyl}-2-(isopropylsulfonyl)anisoleoxalate.

Physicochemical properties:

(i) Melting point: 200°-202° C.

(ii) Elemental analysis for C₂₂ H₃₁ NO₅ S+(COOH)₂ :

    ______________________________________                                                C(%)        H(%)    N(%)                                              ______________________________________                                        Calculated:                                                                             56.35         6.50    2.74                                          Found:    56.60         6.43    2.68                                          ______________________________________                                    

(iii) Nuclear magnetic resonance spectra (d₆ -DMSO):

    ______________________________________                                        δ:                                                                                 ##STR50##                                                                     ##STR51##                                                                     ##STR52##                                                          ______________________________________                                    

The compounds of this invention can be administered orally orparenterally but intranenous injection or oral administration ispreferred. The compounds of this invention are used as the free bases orthe pharmacologically acceptable salts thereof and, in general, they areused as medical or pharmaceutical compositions with carriers or diluentswhich can be used generally for preparing medicaments.

In the case of oral administration, it is most convenient to use themedical compositions of this invention in the form of capsules ortablets but they may also be used as a sustained release preparation.Furthermore, the compositions may be used as sugarcoated preparations orsyrups. The doses thereof at oral administration depend on the kind ofdisease, the age of the patient, etc. Generally, it is proper toadminister 0.005-0.03 mg per single dose of the compound several timesper day in case of intravenous administration or 200-2000 mg of thecompound in two or three times per day case of oral administration.

Example A

Medical composition--tablet for oral administration.

Formulation for 1,000 tablets:

Active component: 100 g

Starch: 185 g

Milk Sugar: 25 g

Magnesium stearate: 1.5 g

The components shown were granulated in ordinary manner using starchpaste as a binder and then molded into tablets each having 9.5 mmdiameter.

What we claim is:
 1. A pharmaceutical composition useful for producingan antihypertensive action based solely on an alpha-adrenergic action,said composition comprised of a therapeutically effective amount of4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfonyl)anisoleor its hydrochloric acid salt and a pharmaceutically acceptableexcipient or diluent therefor.
 2. The pharmaceutical composition ofclaim 1 which contains as said therapeutically effective amount, insingle dose form, from about 0.01 mg to about 100 mg of said anisole orits hydrochloric acid salt.
 3. The pharmaceutical composition of claim 1which contains4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfonyl)anisole.4. The pharmaceutical composition of claim 1 which contains4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfonyl)anisolehydrochloride.
 5. A method of producing an antihypertensive action basedsolely upon an alpha-adrenergic action by administering atherapeutically effective amount of4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylenthyl}-2-(methylsulfonyl)anisoleor its hydrochloric acid salt.